Methamphetamine (METH) abuse continues to escalate and effective treatments are not yet available. METH interacts with the vesicular monoamine transporter (VMAT2), promoting both dopamine (DA) release into the cytosol and reversal of the DA transporter (DAT) to increase extracellular DA concentrations, which is thought to be associated with its abuse liability. Importantly, progress on the current project has shown that alpha-lobeline (LOB) has high affinity for the [3H]dihydrotetrabenazine binding site on VMAT2 and potently inhibits [3H]DA uptake into synaptic vesicles. We have also shown that LOB inhibits METH-evoked DA release in vitro and METH self-administration in rats. Thus, LOB has potential as a new therapeutic agent for the treatment of METH abuse, and has recently successfully completed Phase 1 a clinical trials. However, LOB has been shown to interact with many different CMS targets (i.e. it is a relatively nonselective or "dirty" drug), including alpha4beta2*, alpha6abeta2* and alpha3beta4* nicotinic acetylcholine receptors. In the current proposal, we aim to develop LOB analogs with high affinity and selectivity for VMAT2, which we believe will have increased benefits over LOB as therapeutic candidates for the treatment of METH abuse. We chose VMAT2 as the target as it is a key point of regulation in DA synaptic transmission, due to the high affinity of LOB for VMAT2, and due to METH's interaction with VMAT2, which results in increased extracellular DA that is associated with its reward and abuse. Thus, our hypothesis focuses on VMAT2 as a novel therapeutic target for the treatment of METH abuse. Development of selective, high affinity VMAT2 inhibitors will allow us to test the hypothesis that selective inhibition of VMAT2 decreases METH reward. We have identified lobelane as our lead compound due to its high affinity and relative selectivity for VMAT2, its ability to inhibit METH-evoked DA release, and its ability to decrease METH self-administration. Thus, the long-term goal of this research is to develop novel lobelane analogs as treatments for METH abuse, pioneering the development of a novel class of therapeutic agents that selectively target VMAT2 and have potential as efficacious treatments for METH abuse.